Journal Article

Estrogenic status modulates aryl hydrocarbon receptor—mediated hepatic gene expression and carcinogenicity

Rohit Singhal, Kartik Shankar, Thomas M. Badger and Martin J. Ronis

in Carcinogenesis

Volume 29, issue 2, pages 227-236
Published in print February 2008 | ISSN: 0143-3334
Published online January 2008 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgm288

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Estrogenic status is thought to influence the cancer risk in women and has been reported to affect toxicity of carcinogenic polycyclic aromatic hydrocarbons (PAHs) in animals. The objective of this study was to examine the influence of estradiol (E2) on hepatic gene expression changes mediated by 7,12-dimethylbenz(a)anthracene (DMBA), a potent PAH. Sprague–Dawley rats were ovariectomized on postnatal day 50 and infused with E2 (5 μg/kg/day) or polyethylene glycol using osmotic pumps and 14 days later gavaged with DMBA (50 mg/kg) or sesame oil and killed 24 h thereafter. To understand the mechanism of DMBA-mediated hepatocarcinogenicity in the presence of E2, microarray analysis (Rat 230 2.0 Affymetrix-GeneChip) was performed. Two hundred and sixteen genes were downregulated; whereas, 106 genes were upregulated significantly (±1.5-fold, P < 0.05) by DMBA treatment. Hierarchical clustering revealed that the expression profile of 39 genes, regulated by DMBA, was significantly modified by E2 supplementation. Interestingly, 71 genes were uniquely modulated in the combined treatment of DMBA and E2, but not by either treatment alone. Results from chromatin immunoprecipitation assay demonstrate that in animals cotreated with E2 and DMBA, there was enhanced recruitment of estrogen receptor-α to the regulatory regions of CYP1A1 and aryl hydrocarbon receptor (AhR) genes compared with that observed in animals treated with DMBA alone. E2 supplementation leads to increased DMBA-induced CYP1A1 transcription, while the AhR gene was upregulated in the presence of E2 +DMBA only. Our data suggest that estrogenic status is (i) important in AhR regulation and can influence the effects of xenobiotics and (ii) may be an important factor in DMBA-mediated carcinogenicity.

Journal Article.  6646 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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